Deficits in prefrontal cortex (PFC) function such as poor working memory and attention regulation are common features of many cognitive disorders, including age-related cognitive decline and Attention Deficit Hyperactivity Disorder (ADHD). We posit that PFC deficits arise in large part form the PFC's sensitivity to its neurochemical environment. The proposed research will perform a detailed study of the adrenergic receptor mechanisms influencing PFC function, the second messenger mechanisms initiated by these receptor actions, and changes in these mechanisms with age. Our previous research identified important beneficial noradrenergic (NE) actions at postsynaptic alpha-2 receptors in the PFC. Aim 1 will focus on alpha-1 and beta adrenergic mechanisms in the PFC, as little is known about actions at these receptors. Alpha-1 or beta agonists or antagonists will be infused in the PFC of young vs. aged rats, or administered systemically to young vs. aged monkeys. Results suggest that high levels of alpha-1 receptor stimulation (eg during stress) markedly impair PFC function, and very old animals may be particularly susceptible to these detrimental actions. Alpha-1 mediated deficits are blocked by Li+ pretreatment, indicating actions via PKC signaling pathways. Aim 2 will provide the first study of second messenger influences on PFC function, and how these pathways change with age. We will examine this issue by: a) correlating levels of adenylyl cyclase, PKA/PKC and CREB in the rat PFC with monoamine turnover and cognitive status across the lifespan; and b) determining how intraPFC infusions of agents that stimulate or inhibit PKA or PKC pathways alter PFC function under basal and drug conditions. Initial results suggest the exciting possibility that detrimental PKA/PKC actions may be disinhibited in the aged PFC. Aim 3 will use alpha-2 receptor subtype knockout mice to further characterize the receptor mechanisms underlying the beneficial effects of alpha-2 agonists. Based on our research, the alpha-2 agonist, guanfacine, is now used to treat ADHD, but side effects still limit use in the elderly. Better understanding guanfacine's receptor actions is critical for the design of superior alpha-2 agonists. Finally, Aim 4 will use SPECT imaging in monkeys to visualize the cortical circuits altered by guanfacine treatment. We will test the hypothesis that guanfacine's beneficial effects are specific to the PFC, yet varied within the PFC based upon cognitive demands. Understanding these important adrenergic actions will help to elucidate the prevalence of PFC deficits in neuropsychiatric and age-related cognitive disorders, and will continue to provide new strategies for treatments of cognitive dysfunction.